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SECTION 5.

0
XIENCE V EVEROLIMUS ELUTING CORONARY STENT SYSTEM DESCRIPTION
The XIENCE"V Everolimus Eluting Coronary Stent System (EECSS)is a combination
product comprised of a device (stent system)and a drug coating (everolimusin a polymer
coating). The XIENCE V EECSS was designed to meet several key performance objectives.
The FDA approved and proven MUTLI-LINK VISION and MULTI-LINK MINI VISION
Coronary Systems were chosen because these systems offered a flexible stent with thin
struts and Stent
excellent deliverability. A thin,biocompatibility drug coating was also very
important. The drug coating components were chosen because these materials were efficacious
with reduced drug loading,stable polymers,offered robust coating integrity,and were shown to
be both hemocompatible and compatible with coronary vasculature.
MULTI-LINKMULTI-LINK MULTI-LINK
VISION or
VISION or
L-605
The XIENCE V RX EECSS consists of the coated Cobalt Chromium (CoCr)alloy
MULTI-LINK
MINI VISION stent mounted on a
MINI VISION RX delivery system,respectively. Similarly,the
RX
MULTI-LINK MULTI-LINKMULTI-LINKMULTI-LINK
XIENCE V OTW EECSS consists of the coated
VISION stent mounted on a
OTW delivery system,respectively.
OTW VISION or
VISION or
MINI VISION
MINI

5.1 Stent
L-605
The XIENCE V Everolimus Eluting Coronary Stent (EECS)is a balloon expandable stent
fabricated from a single piece of medical grade Cobalt Chromium (CoCr)alloy.
This alloy can be formed into thinner stent struts than traditional stainless steel stents,and
provides a more flexible,low delivery system profile while maintaining adequate
radiopacity and strength.
Design
There are two stent designs for the XIENCE V EECS:small and medium.The small
(2.5,2.75,2.5 3.0 MULTI-LINK
XIENCE V stent design and mm diameters)is identical toVISION the MULTI-
LINK MINI VISION stent for the diameter,and the

5-1
the medium
3.0
2.75 MULTI-LINK
the mm and mm diameter. The medium XIENCE V stent design is identical to
8-28
3.5 4.0
VISION stent for the mm and mm diameters. All
stent diameters will be available in mm lengths as shown in Table
Table The XIENCE V Stent Sizes
Stent Design Predicate Platform Stent Diameter Stent Lengths
5-1. stent for

2.753.02.5
(mm) (mm)
Small MINI VISION
VISION
8,8,12,12,15,15,18,18,23,23,2828
Medium
VISION
VISION
VISION 4.03.5 8,8,8,12,12,12,15,15,15,18,18,18,23,23,23,282828
features 55--13
for both the small and medium XIENCE V stents. Figure shows digital 5-2
Figure includes the stent expansion diameters,stent free area and several stent design
photographs of the small XIENCE V stent in its crimped and expanded state. Similarly,
Figure shows photographs of the medium XIENCE V stent in its crimped and
expanded state.
Small XIENCE V Stent Medium XIENCE V Stent

Expansion
Material
Expansion
L2.-56,02.75,5Cobalt-Chromium
Balloon expandable
alloy
(CoCr)
and 3.0(post-dilated to
Expansion
Material
Expansion
L3.5-6and05Cobalt-Chromium
Balloon expandable
alloy
(CoCr)
4.0(post-dilated 4.5)
to
Diameters
(mm)
3.5) Diameters
(mm)
Lengths (mm) 8,12,15,18,23,and 28 Lengths (mm) 8,12,15,18,23,and 28
Number of 6
Crests per Crests per Number of 9
Ring Ring
Number of
Links per Ring
3 Number of 3
Links per Ring
Strut
Thickness
(inch)
Figure 5-1 0.0032
thickness,
Strut
Thickness
(inch)
0.0032
Description of the XIENCE V EECSS Stent Designs: The length,strut
and number of links per ring are identical across designs
while the expansion diameter and number of crests per ring varies.
A. B.

Figure 5-2 -
Small XIENCE V Stent Digital photographs showing the small XIENCE V stent in A)crimped and B)
expanded forms
Material
L-605 F90. L-605
The XIENCE V EECS is comprised of medical grade cobalt chromium (CoCr)
alloy tubing conforming to ASTM Standard A majority of the ASTM standards
and test methods for CoCr alloy tubing generally refer to bar, wire,sheet,and
strip testing. Abbott Vascular has adopted the relevant sections of these standards to
ensure compliance with ASTM Standard F90.
5.2 Delivery System Platforms
The XIENCE V EECSS delivery system will be available in two platforms: the
(Over-the-Wire
XIENCE V RX EECSS (Rapid Exchange (RX))and the XIENCE V OTW EECSS
(OTW)).The balloon portions of these delivery systems are identical,
proximal ends
platform. 5-4
the distal portions of these systems are identical in design and materials, and the
are specifically designed to accommodate either the RX or OTW
Figure is a diagram of XIENCE V RX and OTW EECSS components.
Coil Clip Nosepiece Adaption Cup Jacketed Hypotube Intermediate Shaft

A. XIENCE

PEEK Mid Shaft Inner Member Balloon Stent Soft Tip

Polycarbonate Adapter White Foil Markers

Distal Shaft Balloon Markers

B. XIENCE
Nylon Blend Proximal Shaft

Proximal Shaft
Hydrophilic Coating

Common Distal Shaft
Hydrophilic Coating

Figure 5-4 Similarities and Differences in Design between the XIENCE V RX and XIENCE V OTW EECSS. A diagram
detailing A)XIENCE V RX and B)XIENCE V OTW Everolimus Eluting Coronary Stent System (EECSS).
The proximal shaft comprises the unique features of these systems while the distal shaft is identical.
5The.2.1XIENCEThe RapidV RXExchange
(RX) Delivery System
EECSS is similar in design and performance specifications
CSS.MULTI-LINK RX VISION CSS and the MULTI-LINK MINI VISION
to the
RX
Design
Like other Abbott Vascular RX coronary stent systems and coronary dilatation
catheters,
exchange mid-shaft co-axial
the XIENCE V RX EECSS combines a single lumen proximal shaft
with a dual lumen
capability. and a lumen distal shaft to create the rapid
The single lumen proximal shaft connects the
intermediate/distal shaft with the inflation port of the catheter. The guide wire
5-5lumen.
cm. mid-shaft
exit notch is located at the proximal end of the junction between the
intermediate shaft and the support. The overall length of the catheter
is 143 Figure illustrates the components and dimensions.
A single arm adapter is attached to the proximal end of the catheter and accesses
the inflation/deflation The proximal shaft is thermally bonded to an
adaptation cup that is mechanically sealed to the single arm adapter with a
nosepiece,which is threaded to then bonded on the single arm adapter.
There are two non-radiopaque markers on the proximal shaft of the XIENCE V
RX EECSS. The two markers, located 95 cm and 105 cm proximal to the distal
tip, indicate when the distal tip of the catheter exits the tip of a brachial or
femoral guiding catheter,respectively.
A 0.014-inch
lumen. or smaller diameter guide wire can be used in the guide wire
The guide wire exits the guide wire lumen at the guide wire exit notch,
which is formed at the junction of the mid-shaft and the intermediate shafts.
Proximal to this point,the guide wire runs externally alongside the proximal
shaft of the catheter.
Two radiopaque balloon markers located on the distal segment of the inner
member aresuchpositioned to mark the working length of the balloon. The stent is
mounted that the markers reflect the expanded stent length. The
system
5-2
radiopaque markers fluoroscopically aid in positioning the stent and the delivery
for post-deployment dilation during the procedure.
Table includes the product labeling specifications for the XIENCE V RX
EECSS. A detailed protocol for XIENCE V RX EECSS preparation will be
included in the Instructions for Use (IFU)provided with the product.
Coil Clip Nosepiece Adaption Cup Guide Wire Exit Notch Intermediate Shaft Inner Member Balloon Stent Soft Tip

XIENCE

Polycarbonate Adapter White Foil Markers Jacketed Hypotube PEEK Mid Shaft Distal Shaft Balloon Markers

143cm
30 cm
2Proximal
.0 F (0.66Shaftmm) 8,Expanded
12,15,18,Stent23,Length
28 mm

XIENCE

2.9
Intermediate Shaft
F (0.97 mm) 22..47 FF (0.81(0.89 mm)mm)Distal(2.5x8
Shaft
3.0x28mm) 1.6TipF (0.53Entrymm)
5-5
Figure The XIENCE V RX EECSS Components and Dimensions (Notto Scale). All dimensions are nominal.
(3.5x8 4.0x28mm)
Table 5-2
Model
Device Specifications for the XIENCE V RX EECSS
Stent
Number Diameter Stent Crimped Rated Burst System Working
Length Stent Profile Pressure Length
1009539-08
1009539-12 2.5
(mm) (mm)
2.5 8
(in)
0.043
0.043 16
(atm) (cm)
143
1009539-15
1009539-18 2.5
2.5
12
15 0.043
0.043
16
16
143
143
1009539-23
1009539-28 2.5
2.5
18
23
28
0.043
0.043
16
16
16
143
143
143
1009540-08
1009540-12 2.75
2.75 12
8 0.043
0.043 16
16
143
143
1009540-15
1009540-18 2.75
2.75 15
18
0.043
0.043 16
16
143
143
1009540-23
1009540-28 2.75
2.75 23
28
0.043
0.043 16
16
143
143
1009541-08
1009541-12 3.0
3.0 8 0.043
0.043 16 143
1009541-15
1009541-18 3.0
3.0
12
15 0.043
0.043
16
16
143
143
1009541-23
1009541-28 3.0
3.0
18
23
28
0.043
0.043
16
16
16
143
143
143
1009542-08
1009542-12 3.5
3.5 8 0.048
0.048 16 143
1009542-15
1009542-18 3.5
3.5
12
15 0.048
0.048
16
16
143
143
1009542-23
1009542-28 3.5
3.5
18
23
28
0.048
0.048
16
16
16
143
143
143
1009543-08
1009543-12 4.0
4.0 8 0.050
0.050 16 143
1009543-15
1009543-18 4.0
4.0
12
15
18
0.050
0.050
16
16
16
143
143
143
1009543-23
1009543-28 4.0
4.0 23
28
0.050
0.050 16
16
143
143
Note:All dimensions are nominal.
The Over-the-Wire
5The.2.2XIENCE Delivery System
(OTW)
V OTW EECSS is similar in design and performance
MULTI-LINK
specifications to the
MINI VISION OTW CSS.
OTW VISION CSS and the MULTI-LINK
Design
Like other Abbott Vascular OTW coronary stent systems and coronary
dilatation catheters,the XIENCE V OTW EECSS is comprised of a coaxially
tubular inner and outer member. tip.
designed shaft with a balloon near the distal The coaxial shaft consists of a
The annular space between the inner and outer
members provides a lumen for inflating and deflating the balloon; it is accessed
(Figure 5-6).
through the side arm of the proximal adapter. The inner member of the system
wire.
permits the use of a guide The overall length of the catheter is 143cm
A sidearm adapter is attached to the proximal end of the catheter to access the
inflation/deflation lumen and guide wire lumen. A strain relief provides a
transition from the adapter to the shaft.
There are two non-radiopaque
markers on the proximal shaft of the XIENCE V
OTW EECSS located 95cm and 105 cm proximal to the distal These tip.
markers indicate when the distal tip of the catheter exits the tip of a brachial or
femoral guiding catheter,respectively.
0lumen..014-inch
A or smaller diameter guide wire can be used in the guide wire
The guide wire lumen extends from the distal tip to the center port of
the sidearm adapter.
Two radiopaque balloon markers are positioned on the distal segment of the
inner member to mark the working length of the balloon. The stent is mounted
in a manner permitting the markers to reflect the expanded stent length during

5-3
fluoroscopic positioning of the stent as well as in situating the delivery system
for post-deployment dilatation.
Table includes the product labeling specifications for the XIENCE V OTW
EECSS. A detailed protocol for XIENCE V OTW EECSS preparation will be
included in the Instructions for Use (IFU)which will be provided with the
product.
Strain Relief Proximal Shaft Intermediate Shaft Inner Member Balloon Stent Soft Tip

XIENCE

Side Arm Adaptor White Foil Markers Distal Shaft Balloon Markers

143cm

3.2Proximal Shaft
F (1.07 mm) 8,Expanded
12,15,18,Stent23,Length
28 mm

XIENCE

3.3
Intermediate Shaft
F (1.10 mm) 22..64FF(0.86(0.81mm)mm)Distal(2.75x8
Shaft
(2.5x8 2.5x28mm) 1.6TipF (0.53Entrymm)
5-6 2.8 F (0.91 mm)(3.5x23 4.0x28mm)
Figure The XIENCE V OTW EECSS Components and Dimensions (Notto Scale). All dimensions are nominal.
3.5x18mm)
Table 5-3
Device Specifications for the XIENCE V OTW EECSS
Model Stent Stent Crimped Rated Burst System Working
Number Diameter Length Stent Profile Pressure Length
1009545-08
1009545-12 2.5
(mm) (mm)
2.5 8
(in)
0.043
0.043 16
(atm)
143
(cm)

1009545-15
1009545-18 2.5
2.5
12
15 0.043
0.043
16
16
143
143
1009545-23
1009545-28 2.5
2.5
18
23
28
0.043
0.043
16
16
16
143
143
143
1009546-08
1009546-12 2.75
2.75 8
12
0.043
0.043 16
16
143
143
1009546-15
1009546-18 2.75
2.75 15
18
0.043
0.043 16
16
143
143
1009546-23
1009546-28 2.75
2.75 23
28
0.043
0.043 16
16
143
143
1009547-08
1009547-12 3.0
3.0 8 0.043
0.043 16 143
1009547-15
1009547-18 3.0
3.0
12
15 0.043
0.043
16
16
143
143
1009547-23
1009547-28 3.0
3.0
18
23
28
0.043
0.043
16
16
16
143
143
143
1009548-08
1009548-12 3.5
3.5 8 0.048
0.048 16 143
1009548-15
1009548-18 3.5
3.5
12
15 0.048
0.048
16
16
143
143
1009548-23
1009548-28 3.5
3.5
18
23
28
0.048
0.048
16
16
16
143
143
143
1009549-08
1009549-12 4.0
4.0 8 0.050
0.050
16
16
143
143
1009549-15
1009549-18 4.0
4.0
12
15
18
0.050
0.050
16
16
143
143
1009549-23
1009549-28 4.0
4.0 23
28
0.050
0.050
16
16
143
143
Note: All dimensions are nominal.
Materials
The XIENCE V RX EECSS and the MULTI-LINK RX VISION and MINI
VISION RX delivery systems are identical in materials except for the addition
LINK OTW VISION and MINI VISION OTW delivery systems are identical in
materials except fordrugtheforaddition
MULTI-
of the primer and drug matrix polymers and the anti-proliferative drug for the
XIENCE V platform. Similarly,the XIENCE V OTW EECSS and the
of the primer and drug matrix polymers and the
anti-proliferative
stent sheathThismaterial
the XIENCE V platform. There is a difference in
between the XIENCE V and VISION/MINI VISION
systems. sheath material has been evaluated within biocompatibility and
engineering studies with no adverse effect.
5.3 Stent Coating
The XIENCE V EECSS has a coating consisting of two layers:a primer layer and a
layer.
drug matrix The primer layer is composed of an acrylic polymer and has been
approved for other blood contacting applications. The drug matrix layer consists of a
durable copolymer of vinylidene fluoride and hexafluoropropylene
,
blended with the anti-proliferative drug everolimus (Certican Novartis
(PVDF-HFP)
Pharmaceuticals Corporation)in an 83%/17%(w:w)proportion respectively and
applied to the entire surface (ie,luminal and abluminal)of the primer coated
PVDF-HFP is also a component of an approved blood contacting product.
stent.
PVDF-HFP
transplant Certican
65countries. No topcoat layer is used.
microscopy (SEM)images of the coated Figure
expanded states.
5-7
is blended with everolimus,which is under review in the US for the prevention of organ
rejection. (everolimus)has obtained market authorization in over
contains scanned electron
XIENCE V stent in both crimped and
Crimped Expanded

Figure 5-7 Scanned Electron Microscopy (SEM)Images. Images of the coated
XIENCE V stent serpentine rings connected by links in both the crimped
(60x magnification)and expanded (45x magnification)state.
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NEETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\DNEETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\DNEETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\DNEETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\DNEETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\DNEETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\706-506p

RATSETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\.ytilibaemrep

5The.3.1primerThe Primer
coating is used to improve the adhesion between the L-605 CoCr
Coating
alloy MU e primer
ivo1 1
5PVDF-HFP
.3.2 The Drugisa randomMatrixcopolymer made from vinylidene fluoride (VDF)and
hexafluoropropylene (HFP)monomers. The -crystalline with

Cvivo.-F
glass transition and melting temperatures of
VDF unit in the polymer contains one secon
respectively.
ernary
while the HFP unit in the polymer is perfluorinated. The high dissociation
energy
backbone (ie,oxygen,nitrogen,sulfur)renders PVDF-HFP
of the bond coupled with the absence of other atoms in the
resistant
carbon,
to
The

proces -
degradation in Also, contains
and is stable at physiological conditions (Figure Ad
2ion L-605 5-8).
induced degradation,oxidative degradation in vivo,and free radical induced
PVDF-HFP no reactive
strain for the fluoropolymer is approximately
while the Cobalt Chromium hypotube can
functional groups
tion
f 30% its original length. Therefore,coating-related tension failure is
to occur. Due to the dissimilarity of the balloon material (Pebax)
not
and PVDF-HFP
expected
material. polymer, the stent coating does not adhere to the balloon
F

5PVDF-HFP-8
Figure
CH2 CF2

was
n
Copolymer
chosen as
CF2 C
CF3
(PVDF-HFP)
m
Formula for Vinylidene Fluoride and Hexafluoropropylene
the drug matrix polymer because it met the design
objectives for the XIENCE V stent. This material has a history of use in
approved coronary applications and proven vascular compatibility,showed
excellent mechanical coating integrity,was stable in vitro and in vivo,showed
compatible solubility,coatability and sterilizability, was available in a high
purity grade,and demonstrated drug
1 James E, Physical properties of polymers handbook.Woodbury, American Institute of
Mark,1996,
Physics,
2 Baker,R,Controlled Release of Biologically Active Materials, Wiley-Interscience,1987,Chapter
ed. N.Y.:
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NEETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\DNEETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\DNEETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\DNEETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\DNEETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\DNEETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\retpahC

PVDF-HFP worked
number of other well in a simple matrix design,which after evaluating a
release systems,was chosen for the XIENCE V system due to
the good coating quality and integrity,versatility and reproducibility of the
release profile, and ease of manufacturing.
The simple matrix systems consisted of physical blends of drug and PVDF-HFP.
Matrix designs are the most manufacturable. A classical matrix system,with
solid drug dispersed in a matrix of polymer saturated with drug will release the
drug according to a profile that is linear with the square root of time for a
significant fraction of its release3 Developmental studies showed that by
varying the drug to polymer (D:P)ratio and the thickness of the coating,a wide
range of release rates could be achieved,and that these release rates were well
.
controlled and reproducible.

. 5 - 9 .
The release of the drug from the XIENCE V stent as measured in animal studies
is shown in Figure This figure shows how the controlled release of
4 from the XIENCE V stent correlates to the in vivo restenosis
everolimus
cascade

3 Baker,R,Controlled Release of Biologically Active Materials, Wiley-Interscience,1987,
4 al.
Forrester JS et A Paradigm for Restenosis based on Cell Biology:Clues for the Development of New
Preventative Therapies. JACC 1991,Vol 17,No 3,
Xience V In Vivo PK Study
120

100
80

60
40

20
0

Figure 5-95.3.3 0

Release
20 40 60
Time (Days)
80

of Everolimus from the XIENCE V Stent compared to
100

Restenosis Cascade as shown in Animal Pharmacokinetic Studies
The Anti-Proliferative Drug:Everolimus
120 140

[40-O-(2-hydroxyethyl)-rapamycin],
The active pharmaceutical ingredient in the XIENCE V EECS system is
everolimus
Novartis Pharmaceuticals Corporation. Everolimus provided to Abbott Vascular by
is a novel semi-synthetic
macrolide immunosuppressant obtained through chemical modification of
rapamycin. Rapamycin (INN:sirolimus)is a secondary macrolide metabolite
5-10)
produced by certain actinomycete strains. The structure of everolimus (Figure
a 2-hydroxyethyl
consists; ofWyeth)
(Rapamune group in position 40 of sirolimus. Sirolimus
has received global marketing approval for the
prophylaxis of renal transplant rejection. In numerous clinical trials, sirolimus
used as an adjunctive coating on coronary stents,has been shown to prevent
restenosis. A sirolimus-eluting stent has obtained marketing approval in the
European
evaluated
Union, Canada, Japan, US.
and the Everolimus is a drug that has been
in clinical trials in the US and outside the US for use in conjunction
with other medications to prevent heart and renal transplant rejection.
Everolimus (Certican)has obtained market approval in over 65countries.
Additionally,everolimus (Certican)is under review for market approval in the
FDA.
United States and has received two approvable letters from Novartis
continues to work with the FDA towards a final NDA decision using additional
clinical data from prospective transplant trials that evaluate a regimen of
everolimus withUSP)
(cyclosporine, therapeutic drug monitoring and reduced dose Neoral
MODIFIED to support the NDA review.

55.3.-31.01
Figure Structure of Everolimus
Everolimus Mechanism of Action

-
comparison
Inmacrolide with rapamycin,an immunosuppressant of the same class of
compounds,everolimus
toxicity profiles in pre-clinical showed similar systemic exposure and
studies. At the cellular level,everolimus
inhibits growth factor-stimulated cell proliferation in a reversible manner.
FKBP-12. f a c t
At the molecular level,everolimus forms a complex with the cytoplasmic
protein
stimulated phosphorylation of p70 S6 kinase and 4E-BP1,
In the presence of everolimus,the growth o r -
two key players
in the initiation of protein synthesis,is inhibited. Although not formally
proven,itwithis thought
interfere FRAP
that theeverolimus-FKBP-12
(FKBP-12-rapamycin associatedcomplex mayalsobindcalled
protein, and
mTOR, mammalian Target Of Rapamycin) a protein that governs cell
metabolism,
X-ray 4E-BP1.
growth and proliferation, and regulates phosphorylation of
both p70 S6kinase and This is supported by modeling results
using published structure information which suggest that there is no
impediment to the ternary FKBP-12/everolimus/FRAP complex formation.
Everolimus possesses anti-fungal,
immunosuppressive andanti-
proliferating properties. Under the trade name Certican,everolimus has
been studied in preclinical and clinical studies as an anti-rejection therapy
used in combination with Neoral (cyclosporine,CsA). Everolimus is an
effective immunosuppressive agent that can act synergistically with CsA
for the prophylaxis of acute rejection while concomitantly preventing
smooth muscle cell proliferation at the level of the graft vessel.
5.3.3.2
Overview
Summary of Novartis Preclinical Data on Certican
of Preclinical Studies
solid organ transplantation was demonstrated in rodent and non-human
The potential of everolimus as an immunosuppressant in the indication of
primate models of solid organ allotransplantation using an experimental
microemulsion formulation of everolimus for oral application of the
compound. Everolimus was well tolerated after single oral administration
in acute toxicity studies,and therefore,it has a low potential to affect vital
functions following accidental or deliberate overdosing.
In repeated-dose toxicity studies,effects secondary to immunosuppression
higher dosages in all species,and indicate a potential of
were evidenttoatexacerbate
everolimus infectious background diseases. Major target
organs in all animal species were reproductive organs,and males were
generally more affected than females. Lesions were most probably related
to an endocrine imbalance. This was evidenced in rats by a decrease in
plasma testosterone levels as a consequence of an inhibition of key
regulators of steroid hormone synthesis. Lungs (increased alveolar
macrophages)were identified as rodent-specific target organs,and eyes
(lenticular anterior suture line opacities)as rat-specific target organs.
Everolimus was devoid of mutagenic or clastogenic activity, and did not
show an oncogenic
everolimus was potential. In reproduction studies,orally administered
toxic to the conceptus in rats and rabbits. It is therefore
recommendedmeasures that women of childbearing potential should use effective
contraceptive during the entire treatment period. If women are in
early pregnancy when treatment starts,they should be informed about the
potential risk to the fetus. In view of the absence of genotoxic effects and
the results from male fertility studies, male patients who receive treatment
with everolimus should not be prohibited from attempting to father
children.
In the mouse and rat 104-week
Carcinogenicity Studies
carcinogenicity studies,there was no
0.9
everolimus, 8.6 0.3,man.
indication of a tumorigenic potential up to the high dose of mg/kg of
corresponding to an exposure ratio of and respectively,
relative to the maximum recommended dose of 3 mg/day for
13-week
InReproductive
the
Toxicology Studies
male fertility study in rats, no treatment-related effects
0.1 0.5
noted at the lowest dose of mg/kg. At mg/kg,a slight effect
onweretesticular morphology was detected,but there was no difference from
in animals after 13weeks of recovery. There were no adverse
controls
effects on reproductive parameters at this dose. At the highest dose of
males mated,but none of the females became pregnant. Males at 5.0
5.0
mg/kg,
mg/kg showed marked histopathological changes in the testes (atrophy
with germ cell depletion)and epididymides (oligospermia to aspermia).
Sperm
testosterone
period, levels were significantly reduced. After a13-week
motility and testicular sperm head count were diminished.Plasma
recovery
reversibility of the histopathological changes was complete in only
half of the animals,and pregnancy was confirmed in 13/18 inseminated
females mated with the treated males. There was no evidence of adverse
effects by treating males with everolimus on embryo-fetal parameters.
Female fertility was not affected, but everolimus crossed the placenta, and
was toxic to the conceptus. In rats,everolimus caused embryo/fetotoxicity
that was manifested as mortality and reduced fetal weight. Increased
incidence of skeletal retardation,fetuses with 14ribs and spontaneous
malformations was reported. In rabbits, embryotoxicity was evidenced by
pre- post-natal
an increase in late resorptions.
Effects of everolimus on the and
not indicate a specific toxic potential.
Mutagenicity Studies
development of rats did
Everolimus
vivo was
tests,coveringtested for genotoxic activity in a variety of in vitro and in
all relevant endpoints. There was no evidence of a
mutagenic or clastogenic activity. Everolimus exposure in the mouse at
the doses used in the micronucleus assay was well in excess of that
expected at therapeutic doses in humans.
Special and Combination Toxicity Studies
Everolimus did not show a potential to cause contact hypersensitivity on
the skin of guinea pigs in the maximization test. Everolimus was not
irritating to the skin of rabbits.
The administration of everolimus in combination with CsA to rats and
monkeys resulted
compounds, changesreflecting
and ininfindings related to the pharmacological activity of the
toxicity, both notably exacerbated
when compared
There were no newto those observed with each of the compounds alone.
rat.
target organs in the
Monkeys treated with combinations of everolimus and CsA showed
unexpected findings of hemorrhage and arteritis in several organs
(gastrointestinal tract [GI]tract,heart,liver,kidneys,lymph nodes and
pancreas). In view of the complexity of the possible involved mechanisms,
the pathogenesis of arteritis remains uncertain,although the high degree of
immunosuppression
could suggest an infectious/inflammatory origin. The low-dose
in connection with a disturbed integrity of the gut
NEETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\DNEETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\DNEETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\DNEETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\DNEETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\DNEETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\fo

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NEETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\DNEETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\DNEETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\DNEETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\DNEETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\DNEETONTOOF_RR\\REKRAMRR\\TRATSETONTOOF_RR\\REKRAMRR\\.236-726:)5(72

combination of CsA/everolimus at 50/0.25 mg/kg resulted in a higher
degree of immunosuppression than with the compounds alone,but was not
associated with arteritis or poor health status as observed with the
dose combinations. high-
The combination of everolimus and tacrolimus in rats induced an increased
severity of adverse effects and of changes related to immunosuppression
when compared with those of either compound alone. The increase in
reproductive systems. With the
tacrolimus, 0.75 low-dose
toxicity was particularly pronounced in the cardiovascular and
combination of everolimus and
both at mg/kg,there was,however,only slight increases
in severity compared with each compound alone. The combination had no
relevant effect on the toxicokinetic profile of tacrolimus,whereas exposure
with everolimus was markedly increased.
Absorption and Bioavailability
low oral doses,was affected by intestinal
Caco-2 .P-gp
A significant proportion of the absorbed everolimus in the rat, especially
first-pas 14%-26%
metabolism The
absolute bioavailability of everolimus was 5%in the mouse,
5
in
at

everolimus was
concentrations, .
the rat and 6%in the monkey. Studies in
a substrate for
cells showed that
the efflux transporter at low
but that this efflux was saturated at higher
concentrations6 5 The absolute bioavailability of everolimus could not be
assessed in man
formulation due to the difficulties
for intravenous administration, and since no
level was identified in the intravenous monkey studies.
non-toxic
in providing an appropriate
effect
Distribution
The in vitro distribution of everolimus between blood cells and plasma was
concentration dependent over the range of 5 to 5000 ng/mL in the rat,
monkey and human, and concentration independent in the mouse.
Everolimus was highly bound to plasma proteins of the mouse (99.9%),
and moderately bound in the rat (92%),monkey (84%)and human (75%).
that a potential
very unlikely. drug-drug
The moderate affinity of everolimus for human plasma proteins indicates
interaction on the basis of drug protein binding is
The extent of protein binding was similar between healthy
humans and patients with moderate hepatic impairment.

5 Crowe A,and
SDZ-RAD Bruelisauer A,inDuerrrats.L,Druget alMetab Dispos;
rapamycin (1999) Absorption and intestinal metabolism
6 Crowe A,Lemaire M In vitro and in vivo absorption of SDZ RAD using a human intestinal cell
line(Caco-2)and a single pass perfusion model in rats:Comparison with rapamycin.Pharm Res;15:1666-
(1998)
44:2027-2034\\RRMARKER\\RR_FOOTNOTESTART\\RRMARKER\\RR_FOOTNOTEEND\\RRMARKER\\RR_FOOTNOTESTART\\RRMARKER\\RR_FOOTNOTEEND\\RRMARKER\\RR_FOOTNOTESTART\\RRMARKER\\RR_FOOTNOTEEND\\RRMARKER\\RR_FOOTNOTESTART\\RRMARKER\\RR_FOOTNOTEEND\\RRMARKER\\RR_FOOTNOTESTART\\RRMARKER\\RR_FOOTNOTEEND\\RRMARKER\\RR_FOOTNOTESTART\\RRMARKER\\RR_FOOTNOTEEND.

Metabolism
The metabolism of everolimus was investigated in the mouse,rat and
monkey after single oral and intravenous In humans,the
metabolism of everolimus was investigated in stable14renal transplant
doses.
patients on Neoral after a single oral dose of 3 mg [ C]everolimus.
all species,generally,the parent drug was the major circulating
Incomponent in blood,averaging of the total AUC h)
radioactivity in mice,rats and humans and 12% in the monkey.In human
31%-63% (0-24
blood, 5 major metabolite peaks were14 present covering,together with
unchanged drug,> 80%of the total These 5 main metabolites
detected in human blood were also present in the blood of the mouse,rat
and monkey.
C-AUC.
Excretion/Elimination
Excretion of everolimus and its metabolites was predominantly via feces in
all investigated species,including man,and was characterized by
metabolic clearance. Virtually no parent drug was recovered in the urine
and
days.feces. The balance of excretion was almost complete within several
Drug-Drug
The potential for metabolic drug-drug interactions was investigated in vitro
Interaction Potential

.2.3 2 -
protein)
3
in human liver microsomes,and in microsomes from recombinant CHO
cells expressing individual cytochrome P450 isoenzymes. CYP3A4 was
the major P450 enzyme involved in the microsomal biotransformation of
everolimus
7

Everolimus
6
(Km mol/L; V max
wasanda was
nmol/h/mg microsomal
competitive inhibitor of the CYP3A substrate CsA (Ki
46-10
=
mol/L), also a mixed inhibitor of the CYP2D6 substrate
dextromethorphan (Ki mol/L). The maximum plasma concentration
following a daily recommended highest oral dose of mg bid of
= 1.7 20.3 8.0 1.5
75-fold
everolimus in human (C ss: ng/mL)was,however, more than
below these K i max Therefore,everolimus is unlikely to
significantly affect the metabolism of other compounds predominantly
cleared by these enzymes.
-values.
Prevention of Vascular Proliferation
Everolimus
smooth
inhibited in vitro fetal calf
muscle cell bovine aortic
(SMC)proliferation. Oral administration of
serum-stimulated
everolimus
inhibited
mg/kg/day, beginning 3 days before vessel injury)to pigs
intimal thickening by 54%and neointimal area by
(1.0
PTCA-induced
7Kuhn B,Jacobsen W,Christians U,et al (2001)Metabolism of sirolimus and its derivative everolimus by
cytochrome P450 3A4:Insights from docking,molecular dynamics and quantum chemical calculations. J
Med Chem;
34%. Additionally,everolimus was efficacious in a rabbit stent model.
Rabbits were treated with 2 different oral dosing regimens of everolimus in
combination with arterial stenting. The high dose regimen consisted of 1.5
1.0 1.5
mg/kg/day beginning 3 days prior to stenting and continuing for 14days
following stenting,after which the dose was reduced to mg/kg/day for
the remainder of the study. The low dose regimen consisted of
mg/kg/day the day before surgery,which was then reduced to 0.75
mg/kg/day for the remainder of the study. At 28 days post stenting both
groups showed 84%endothelialization of the stent. Both treatment
regimens
dose
significantly reduced neointimal thickness (by49% for the high
for the low dose)and neointimal area (by32% for the high
dose and
and 40%
24% for the low dose).
These data supported the further investigation of everolimus as a potential
therapeutic agent for the reduction of restenosis following PTCA and
stenting.
associated
In order to avoid the potential side effects and large doses
with oral administration of everolimus,Abbott Vascular has
studied the safety and potential utility of everolimus eluting stents for the
prevention of restenosis.
5.3.3.3 Summary of Novartis Clinical Data on Certican
The purpose of the following discussion is to summarize the safety and
efficacy of systemically administered everolimus. Everolimus has been
in lung and liver transplant patients. Therapeutic doses between and1.5 3.0
studied extensively in renal and heart transplantation with additional date
mg/day have been thoroughly evaluated. The use of everolimus in heart
transplant studies showed significantly less thickening of the intima in the
coronary
group. arteries of transplanted patients in comparison with the control
These findings support the safety and efficacy of everolimus at
doses that exceed the levels eluted from the XIENCE stent. The following
data are from Novartis Investigator s Brochure,Edition 9,dated August
27, 2007.
Everolimus, 3.0
at therapeutic blood levels greater than ng/ml,has been
shown to be an effective immunosuppressant that has been developed for
use in combination with Neoral (cyclosporine,USP)MODIFIED for the
prophylaxis of acute rejection and the prevention of chronic rejection in
patients receiving organ transplants. The following is a summary of
clinical trials, demonstrating the safety profile of systemic therapeutic
levels 3.0
of everolimus greater than ng/ml. Accordingly,the blood levels
transplant ten-fold
of everolimus achieved with oral doses used in clinical trials of organ
rejection are approximately
systemic exposure with the implantation of XIENCE. higher than the total in vivo
In humans,everolimus dosed twice daily (bid)with CsA yields
state
steady-
drug exposure by day 4 after initiation of therapy in renal and heart
transplant recipients. Thereafter,blood levels of drug remain relatively
constant over time through the first post-transplant year. There are no
clinically relevant departures from dose proportionality in exposure.
Freedom from acute rejection in both renal and heart transplantation is
significantly related to everolimus trough concentrations with a lower
therapeutic concentration threshold of 3 ng/mL. There is only a small
additional increase in freedom from rejection at everolimus trough levels
above 8 ng/mL. Although the incidence of decreased thrombocyte counts
(<75to 100 x 109 /L)increases with increasing exposure,the overall
incidence in clinical trials was low,and therefore,a precise upper
concentration for the therapeutic range could not be identified based on
safety concerns. Clinical experience with trough concentrations above 12
range 1.5
ng/mL or doses above mg bid is limited. The therapeutic concentration
is recommended as 3 to 8 ng/mL in both kidney and heart
transplantation.
Use of Everolimus in Renal Transplantation
Efficacy Summary
In de novo renal transplant patients, both doses of everolimus combined
with ful -dose Neoral had similar efficacy as compared with
rejection, graft loss,death,or loss tofollow-up) (biopsy-proven
mycophenolate mofetil (MMF)for efficacy failure acute
at 6 and 12months,and
were comparable at 36 months. The therapeutic drug monitoring analyses
strongly suggest that graft survival would be improved with the use of
everolimus concentration monitoring. Patient survival was excellent in all
groups.
Inof studies B251 and B201 in de novo renal transplant patients, both doses
everolimus (1.5 and 3 mg/day)administered in combination with Neoral
and corticosteroids was equivalent to MMF with respect to efficacy failure
at 6 months post-transplantation (ie,
loss, death,or loss to biopsy-proven
fol ow-up). co-primary acute rejection,
for efficacy
Equivalenceendpoint
graft
failure was
maintained at 12months. For the of graft loss,death,

--
or loss tofollow-up at 12months post-transplantation,in study B251
95% and 97.5% confidence intervals (CIs)for everolimus mg MMF1.5 vs.
(mostly US centers),everolimus 3 mg was equivalent to MMF,and both
slightly exceeded the limit of equivalence. In study B201 (mostly
European centers), 1.5 vs.
everolimus mg was equivalent to MMF,and both
95% and 97.5% CIs for everolimus 3 mg MMF slightly exceeded the
biopsy-proven
limit of equivalence. The incidence of late-occurring
rejections (ie,days 451 to 1170)was low in all groups. Between 1 and
acute
1170 days,the incidence of deaths was similar in all groups for studies
1.5
B251 and B201,respectively: everolimus mg 12patients (6%)/ 15
patients (8%),everolimus 3 mg 13patients (7%)/ 18 patients (9%),and
MMF 10 patients (5%)/ 16patients (8%).
As the use of everolimus with ful -dose Neoral is associated with renal
dysfunction in some renal patients,it has been important to recognize that
the efficacy of everolimus is maintained in combination with
Neoral. reduced-dose
This was initially demonstrated in study B156,a prospective trial
using the 3 mg/day dose of everolimus,in which rejection efficacy
remained excellent despite reduction of Neoral exposure by about 35%.
Amendments
rare when CsA trough levels were reduced to about 75 ng/mL at
f u l -
months after transplantation. This studygroups,
both the Neoral and reduced-dose demonstrated
18-31
to the Phase 3 studies showed that late rejection was very
excellent efficacy in
thus demonstrating that
efficacy is maintained when CsA exposure is reduced in combination with
everolimus.
The most recent renal studies A2306 (withoutSimulect)and A2307 (with
Simulect induction),which both used TDM prospectively, demonstrated
better renal function,at 12months,than that previously observed in the
1.5
phase 3 studies,B251,B201 and B156. Everolimus and 3 mg in
combination with corticosteroids and a reduced Neoral dose regimen was
12months
proven
observed
post-transplant.
acute biopsy-
effective in the prevention of graft rejection after renal transplantation at
The incidence of efficacy failure and
rejection was low in both studies,and comparable to that
in the pivotal studies,B251 and B201,and study B156. Long
term outcomes at 36 months in the A2306 and A2307 extensions were
similar to those at 12months and no statistically significant differences
between groups were observed in efficacy and safety parameters.
InSafety Summary
de novo renal transplant patients, both fixed doses of everolimus (1.5
mg and 3 mg)were generally
towards a well-tolerated, although there was a tendency
higher incidence of nonfatal SAEs and discontinuations of study
medication due to AEs with everolimus compared with MMF.
Thrombocytopenia was observed more frequently in both everolimus
groups
was comparedwithwithdosetherelated
associated increases ful -dose
MMF group. Everolimus plus CsA
in mean serum creatinine and
decreases
was in creatinine clearance compared with MMF. Mean testosterone
significantly lower in both everolimus groups compared with the
MMF group;however,at 12months, mean testosterone was within the
normal
more range in all treatment groups. Elevations of serum lipids occurred
frequently in everolimus-treated patients than in the MMF group,
with greater changes in the everolimus 3 mg group compared with the
mg group.
1.5
renal study controlled
Inconcentration reduced-dose
a
A2306,witheverolimus, Neoral regimen and
mean and median serum creatinine
was low, and stable from 2 or 3 months onwards to 12months. The
inclusion of only approximately 50%of the original randomized patients
into the extension of this study limits meaningful conclusions made for this
extension.
Use of Everolimus in Heart Transplantation
Efficacy Summary
the heart transplant study B253,both doses of everolimus and 3
Inmg/day) were superior (1.5
to azathioprine (AZA)for efficacy failure (acute
rejection ISHLT e grade 3A,acute rejection associated with hemodynamic
compromise,
months.rejection follow-up)
graft loss,death,or loss to at 6,12,24,and 48
This finding was primarily due to a reduction in the incidence of
acute (ISHLTe grade 3A)in the everolimus groups. As
discussed above for renal transplantation,TDM is expected to enhance the
efficacy and safety of everolimus in heart transplantation. There is a clear
reduction in the incidence of acute rejection with average everolimus
trough levels > 3 ng/mL. A small subset of patients was enrolled up to 72
months prior to study discontinuation. The number of patients was too
small to reach any conclusion of their data.
The heart study also demonstrated a significant reduction in average
maximum intimal thickness of the coronary arteries from baseline at 12
and 24 months for both doses of everolimus compared with the AZA
group. Thus, both doses of everolimus were superior with respect to the
incidence of allograft vasculopathy at 1 year post-transplantation, and the
1.5 mg group was also superior at 24months.
1-3
Everolimus,at fixed doses of 1.5 and 3 mg/day,administered in

- -
combination with Neoral and corticosteroids to primary heart allograft
recipients was superior to a standard treatment with mg/kg/day of AZA
with regard to the incidence of efficacy failure at 6,12,24,and 48 months
and everolimus 3 mg/day was superior to 1.5 mg/day. In particular,
significantly fewer acute rejection episodes were reported in both
48-month dose groups,
everolimuspatient and graftandsurvival was 24-,
this effect was dose related. Twelve, and
excellent in all groups,with no
significant differences between everolimus and AZA. Specifically,in the
l1,530,
everolimus 1.5 32-
ong-tetherm,incidence
open-labelofextension period (48months)between Days 1 and
deaths was similar in all treatment groups:
mg patients (15.3%),everolimus 3 mg 34 patients
(16.1%),and AZA 30patients (14%).
Safety Summary
In de novo heart transplant patients,the incidence of nonfatal SAEs and
discontinuations of study medication due to AEs was significantly higher
1.5
in the 3 mg fixed dose of everolimus compared with the mg fixed dose
of everolimus and azathrioprint. The overall infection rates were
comparable between groups;however,there was a significantly higher
incidence of viral infections (particularly CMV infections)in the AZA
group than in the everolimus groups. Decreases in mean hemoglobin and
platelet counts occurred more frequently in everolimus-treated level.
than in the AZA group,and were associated with everolimus dose
patients
group.
Conversely,leukopenia was more frequent in the AZA Mean LDLs
and HDLs were not significantly different between groups. Mean
triglycerides were elevated in both everolimus groups compared with the
AZA group. Everolimus was associated with dose related increases in
mean serum creatinine and decreases in creatinine clearance that were
significant compared with the AZA group,but these values were stable
from 12to 24 months. Mean testosterone was significantly lower in both
everolimus groups compared with the AZA group.
Use of Everolimus in Lung Transplantation
Efficacy Summary
maintenance
Inunique lung transplant patients (study B159),everolimus showed
progression
syndromeEverolimus
survival. 1-3 long-term
efficacy not only to prevent acute rejection, but also slowed the
in airway dysfunction. The onset of bronchiolitis obliterans
(BOS)in this patient population portends limited
3 mg/day was superior to AZA mg/kg/day for
the primary efficacy endpoint (incidence of FEV1 decline > 15%of the
baseline value from the study entry value,graft loss,death or loss to
follow-up during the first 12months after the initial dose of study
medication).
v s . =
The incidence rates for this composite primary endpoint were
22% and 34% for everolimus 3 mg/day and AZA,respectively (p
0.0455). The incidence rate for FEV1 > 15%was 16% 28%(p=0.034),
v s .
and for treated acute rejection episodes was 8% 32%(p< 0.001),
vs. = v s .
showing a significant advantage of everolimus AZA,while the
incidence of deaths (3% 9%,p 0.061)and all other secondary
efficacy endpoints demonstrated a trend in favor of everolimus. More
AZA patients discontinued study medication due to unsatisfactory
therapeutic effects, while more patients discontinued study medication in
the everolimus group due to AEs.
The primary efficacy endpoint (ie,incidence of FEV1 decline >15% of the
baseline value from study entry value,graft loss,death or loss to follow-up
during the first 12months after the initial dose of study medication)was
difference in favor of everolimus was significant (p = 0.0455).
22% and 34% for everolimus 3 mg/day and AZA,respectively,and the
Graft losses and deaths were numerically lower in the everolimus group.
Everolimus
decline >15% of the baseline value from study entry value (p
Everolimus
and = = 0.034).
was superior to AZA with regard to the incidence of FEV1
was also superior to AZA with regard to the incidence of BOS
decline in FEV1 >15% (p 0.014)and the incidence of treated acute
rejection episodes (p< 0.001). In addition,all other efficacy variables
showed a trend in favor of everolimus.
By 24 months,the incidence of acute rejection remained significantly
lower AZA.
in the everolimus patients as compared to However,the
incidence of the primary composite endpoint did not differ between
treatment groups (everolimus:43.6%;AZA:44.6%)and rates of graft loss
similar.efficacy
and alldeathotherweresecondary
and The incidences of FEV1 >15%(34.7%vs 41.1%)
endpoints were numerically lower in the
regard to thegroup.
everolimus There wasin FEV
mean decline also1 afrom in favor of everolimus with
trendstudy entry to 24 months.
Safety Summary
Everolimus use in lung transplantation (study B159)was associated with
its anticipated side effect profile of CsA nephrotoxicity, lipid elevation,
vsv.s.
clinically silent endocrine abnormalities and an increased risk of infection.
vs. vsv.s.
The incidence of overall infections (82% 80%),bacterial infections
(35% 17%)and fungal infections (28% 14%)were higher in the
the AZA group. At 12months the incidence of viral
everolimus group
infections (30% 29%),and specifically,CMV infections (9% 12%),
was similar in the everolimus and AZA groups,respectively. The
incidence of malignancies was low,and did not show a difference between
vs.
vs.
the everolimus AZA groups (7% 5%).
Use
vs.
of Everolimus in Liver Transplantation
Efficacy Summary
Inthestudy B158 with 119 de novo liver transplant patients,the incidence of
composite endpoint(biopsy-proven and treated acute rejection,graft
loss,
everolimus (1, follow-up
death or lost to at month 12)was similar for all 3 doses of
2 and 3 mg/day)and placebo (50%,43%,42% and 47%,
respectively). No between-group differences were observed for the
individual components of this composite endpoint,although there was a
trend towards2 and
everolimus acute rejection
fewer4 mg/day groups.episodes and fewer deaths in the
In 119 de novo liver transplant patients,the incidence of the composite
endpoint (biopsy-proven and treated acute rejection,graft loss,death or
lost tofollow-up) was similar for all 3 doses of everolimus (1,2 and 4
mg/day)and placebo at month 12and for the 3 doses of everolimus at 36
months. There were no dose-related or statistically significant differences
between treatment groups in the incidence rate of efficacy failure or its
single components. All graft losses and most deaths were secondary to
typical post-transplant complications,and none of them were considered to
be associated with the study medication. Most efficacy-related events
occurred before 12months. No between-group differences were observed
for the individual components of this composite endpoint,although there
was a trend
everolimus towards fewer acute rejection episodes and fewer deaths in the
2 and 4 mg/day groups though 36 months. Pharmacokinetic
modeling, consistent with that observed in renal and cardiac transplant
studies suggests that the risk of acute rejection is associated with the
trough levels of everolimus similar to other solid transplant organs.
Trough levels of everolimus > 3 ng/ml had numerically lower events of
rejection within the first year compared to placebo.
InSafety Summary
study B158 with de novo liver transplant recipients, more patients in the
fixed dose everolimus groups,used with standard doses of cyclosporine,
than in the placebo group discontinued study medication due to TheAEs.
incidence of nonfatal SAEs was slightly higher in the everolimus treated
patients. More patients in the everolimus 2 and 4 mg/day groups showed
notably high total cholesterol levels. More patients reported
hypertriglyceridemia as an AE in the everolimus 2 and 4 mg/day groups
than in the other groups. Acute renal failure occurred more frequently in
the everolimus 2 and 4 mg/day groups. The incidence of hepatic arterial
thrombosis (HAT)was low in this study (2of 89patients in the everolimus
groups and 1 of 30 patients in the placebo group).
Summary and Conclusions of Novartis Clinical Data on Everolimus
summary,
Inlevels Novartis 3.0
clinical trials demonstrate the safety of therapeutic
of everolimus greater than ng/ml. The blood levels of
everolimus achieved with oral doses used in clinical trials of organ
transplant rejection greatly exceed the in vivo systemic exposure with the
implantation of XIENCE V product.
5.4 Packaging Information
Both the XIENCE V RX and OTW systems have a protective sheath that covers the
stent/balloon area and is inserted into a dispenser coil. The dispenser coil is placed into
an inner header bag,which is heat sealed and given a product label. The header bags
are placed into a corrugated shipping box and ethylene oxide (EtO)sterilized.
Post sterilization,each header bag is placed inside an outer foil pouch. First,the foil
sealed, gas.
pouch is purged of ambient air and filled with an inert Next,the pouch is heat
labeled,and placed inside a labeled carton. Individual products in a carton are
placed into suitable corrugated boxes designed to protect the packaged product from
damage during transit.